We examined the neurohumoral mechanisms underlying the hindlimb vasodilator response produced by electrical stimulation of the anteroventral region of the third ventricle (AV3V). Hindlimb blood flow velocity was recorded using a pulsed Doppler flow probe. The vasodilator response to AV3V stimulation was greater than that obtained after inhibition of neurogenic vasoconstrictor tone with sympathectomy and was, therefore, in part an active process. The hindlimb vasodilator response was not affected by cholinergic or histaminergic receptor blockade but was reduced by bilateral adrenalectomy (ADX) or adrenal demedullation (ADM) and was further reduced by beta-adrenergic receptor blockade with propranolol in ADX rats. In ADX or ADM rats the vasodilator response was attenuated by repeated AV3V stimulations and restored by epinephrine infusion. Moreover, restoration of the response after epinephrine infusion was completely blocked by the neuronal uptake blocker desmethylimipramine. As was observed with vasodilation, constrictor responses to AV3V stimulation in the renal and mesenteric vascular beds were also attenuated by adrenal demedullation and were restored by epinephrine infusion. These data suggest that circulating epinephrine, originating in the adrenal medulla, is taken up by sympathetic nerve terminals innervating blood vessels. The catecholamine is then released from these nerves and acts like a classical neurotransmitter, producing vasodilation in skeletal muscle and vasoconstriction in splanchnic and renal vascular beds.